The long term objective of this Brain Tumor Research Center is to improve the therapy of patients afflicted with this devastating disease in the hope of improving survival and decreasing morbidity and mortality. Recognizing that tumor cell heterogeneity is a fundamental obstacle to effective therapy of glioblastoma multiforme, we propose to address the molecule, biological, and pharmacological diversity of these neoplasms in order to coordinate a highly effective multimodal interdisciplinary therapeutic attack on this neoplasm. This proposal consists of two basic science and two clinical Projects. The basic science Projects (1 & 2) are designed to develop diverse antineoplastic agents to be used, in combination, to destroy and heterogeneous sub-populations of cells present in these tumors and to inhibit the neovascularization of these neoplasms. The clinical Projects (3 & 4) are designed to apply the new experimental therapeutic approaches generated in the basic science Projects in a highly focused multidisciplinary assault combining the various treatment modalities of surgery, irradiation and chemotherapy. Project 1 will isolate and characterize various new heterogeneous cell lines obtained from human gliomas in patients operated on at our Center and establish a reference cell bank and nude mouse xenograft models for the detection and investigation of new cytotoxic agents alone and in combination with irradiation. Project 2 will screen and develop novel anti-angiogenic agents, integrated into controlled-release polymer systems, in an effort to arrest tumor proliferation, not by inhibiting the growth of neoplastic cells, but by impairing the development of their blood supply. Project 3 will utilize the combination of stereotactic radiosurgery using the 201 source CO-60 gamma knife together with radioenhancing chemotherapeutic agents developed in Project 1. Project 4 will combine the use of surgery with implanted controlled- release polymer systems developed in Project 2 and designed to deliver new combinations of cytotoxic drugs and novel antiangiogenic agents to prevent the recurrence of neoplastic cells and their revascularization. By providing an interdigitated system of research projects and supporting core units we will be able to translate new therapies resulting from laboratory discoveries rapidly and efficiently to the bedside, as well as to provide effective feedback from clinical investigators to basic scientists. It is our conviction that this integrated multidisciplinary approach is to critical importance in defining and destroying the molecular and pharmacological targets that constitute the intrinsic obstacles to eradicating these malignant heterogeneous neoplasms.